Although most patients with acute myeloid leukemia (AML) achieve complete remission (CR) following standard induction chemotherapy, the majority subsequently relapses and succumbs to the disease. A leukemia stem cell (LSC) paradigm may explain this failure of CR to reliably translate into cure. Leukemia appears to retain some semblance of the normal hematopoietic hierarchical structure: i.e., rare LSCs with self-renewal capacity give rise to partially differentiated progeny that comprise the bulk of the leukemia but possess only limited proliferative potential. It is theorized that existing therapies, although highly active against the leukemic bulk, often spare the hardier LSCs responsible for relapse.
Since the 1994 report by Dick and colleagues that only the rare AML cells characterized by a CD34+CD38− phenotype were capable of generating leukemia in immunodeficient mice, these putative LSCs have been the focus of considerable research. However, even in leukemia where the cancer stem cell (CSC) concept is perhaps best established, there is a paucity of data that LSCs are in fact responsible for disease resistance or relapse. Although it is generally accepted that CD34+CD38− cells are enriched for LSCs, this population is heterogeneous and includes both normal and leukemic cells. Moreover, recent data have challenged the CD34+CD38− phenotype of LSCs in AML, leading many investigators to advocate for a functional definition LSCs: those leukemic cells capable of engrafting immunodeficient mice. However, this current gold standard for the identification of LSCs has proven to be somewhat elusive. A significant fraction of AML samples will not engraft mice, and the assay is cumbersome and often non-quantitative. Additionally, the clinical implications of this assay are unclear.
If CD34+CD38− leukemic cells are indeed clinically relevant, then minimal residual disease (MRD)—any microscopic disease remaining during CR—should be relatively enriched for these cells; and their persistence after therapy should correlate with recurrence.
Therefore, there still exists a need for identifying LSC in patients with AML so that the patients can be identified as having a high or low risk for relapse and appropriate treatment can be delivered.